A delivery system for temporary radiation therapy comprising a sheet of material which is absorbable within the human body and having a plurality of parallel passages therein. The sheet is sutured to an area of the body which is to be treated and a catheter is inserted in each passage and extends to the exterior of the body. A tube carrying a plurality of radioactive seeds dispersed therein is inserted in each catheter. After a period of treatment, the tubes and catheters are removed and the carrier remains in the body.

Interstitial radiation therapy has been performed since the beginning of the 20th Century. Radium was developed by Madam Curie and Alexander Graham Bell proposed the use of radium in tumors. Subsequently, metal needles were developed in which a radium isotope was encapsulated for insertion in close proximity or into tumors. Where the tumor was deep seated, an operation was necessary to provide access to the tumor. Such therapy had serious problems and disadvantages. The high energy of the radium isotope required a great deal of shielding and subjected the personnel to harmful exposure. In addition, the needles tended to break as they aged resulting in the release of the radioactive contents. Since the radium isotopes had a half-life of about 1600 years, they produced an extreme contamination hazard.
Thus, efforts have been made to develop more effective brachytherapy which is safer and more convenient to use. This has resulted in the development of radioactive materials that have lower energies and thus require less shielding and have shorter half-lives to reduce the risk of contamination. Thus, permanent seeds of encapsulated radon-222 having an energy level of 0.78 MEV and a half-life of 33.83 days or of encapsulated gold-198 having an energy level of 0.42 MEV and a half-life of 2.7 days have been used. More recently small seeds of iridium-192 having an energy level of 0.30 MEV and a half-life of 74.2 days and iodine-125 having an energy level of 0.028 MEV and a half-life of 60 days have been developed. Such seeds are shown, for example, in U.S. Pat. Nos. 3,351,049 and 4,323,055.
Such iridium and iodine seeds are on the order of 4.5 mm in length and 0.8 mm in diameter and are implanted in the tumor or placed in the surface of the tumor. Both of these sources have lower energies than radium that allow for simpler shielding and less radiation exposure to personnel. With seeds of iodine encapsulated in a material such as titanium, shielding is provided by the surrounding tissue and the seeds can be left in the patient permanently without the need for major precautions.
Further development in brachytherapy has been the development of techniques for implanting the newer developed radioactive seeds. Two techniques, in general, have been developed to allow further reduction in personnel exposure during the implanting process. The two techniques involved are permanent and temporary implants. Both utilize afterloading techniques where guides in the form of catheters are placed through the tumor mass or on the tumor surface.
Permanent implants usually use sources with a very short half life of a few days or low energy low activity, both resulting in very low exposure to bystanders so the patient can be discharged without fear. Since loose radioactive seeds are utilized, this procedure can only be used by volume implants in an effort to firmly hold the seeds in place. Problems arise if an implant is needed in a volume that will not be able to sustain the seeds in a rigid geometrical position, such as a breast tumor where the breast tissue is flexible. Likewise, the tumor volume only represents a thin layer of tumor cell. Examples include tumors that grow over the surface but invade only minimally the skin or a flat plexus of vessels containing tumor such as the tumor barring lymphatics of the mediastium or the tumor bed when a tumor is removed off of a surface which still harbors malignant cells. This type of implant usually requires a supporting carrier for the radioactive seeds, which must be removed within a specified time, neccessitating a temporary implant. Thus in this technique nylon plastic catheters are sutured on, or pierced through, the tumor volume. The catheters are then loaded by inserting a second nylon catheter of a smaller diameter containing the radioactive seeds. After the desired radiation dose is delivered the two catheters are withdrawn.
The temporary catheter placement for treatment of tumor beds has an ever increasing role in cancer management, as mutilating surgical procedures decrease and post operative irradiation is utilized to treat the scattered cancer cell. Thus the use of placing temporary iridium implants as described above has found a significant role in the treatment of lung tumors. Tumors frequently have to be sharply dissected off of the chest wall, diaphragm, or the central vital organs of the chest. Colon and rectal tumors frequently have to be dissected off of the pelvic bony wall. Although this technique does work, there are inherent problems that this innovation solves while other techniques attempting to solve the problem do not address all the to be described difficulties and do not solve them.
As described above the technique for temporary planar implants involves the suturing of nylon catheters to the tumor bed after the removal of the cancer while the patient is under general anesthesia. The method is well described by Hilaris et al, "Value of Perioperative Brachytherapy in the Management of Non-Oat Cell Carcinoma of the Lungs", Int. J. Radiation Oncology Biol. Phys.; Vol. 9, pp. 1161-1166, (1983). Each catheter should be sutured in three to four places. This is a time consuming procedure which uses expensive operating time as well as increasing the patient's risks. This problem is compounded if the implant needs to be performed in a tight area or awkward position. The catheters cannot be sutured at all when removal of the tumor is so complete as not to leave tissue to suture the catheters to. An example of this would include a pelvic tumor removed leaving only pelvic bone riddled with cancer cells. Since these catheters are anchored in only at a few points along their path, yet need to follow a irregular surface, the catheters tend to lose the parallel spacing between them, resulting in areas where the catheters become bunched together, and a resultant relative hot spot and causing radiation overdose with necrosis, while leaving an area of underdosage where a tumor recurrence can occur. An overdose over a critical area such as the spinal cord can leave a patient crippled for life, while tumor recurrence will cause the patient's death.
Another technique described by Martinez et al, "Sterilization of .sup.125 I Seeds Encased in Vicryl Sutures for Permanent Interstitial Implementation", Int. J. Radiation Oncology Biol. Phys.; Vol. 5, pp. 411-413 (1979) utilizes Iodine-125 seeds spaced within a braided absorbable polymer surgical suture (Vicryl). Although this technique allows for a permanent planar implant in areas described above, still maintains the many of the above problems of time consumption of placing individual sutures, including inability to implant denuded areas, and ability to maintain exact parallelism between the ribbons.
Another technique by Marchese et al, "A Versatile Permanent Planar Implant Technique Utilizing Iodine-125 Seeds Imbedded in Gelfoam", Int. J. Radiation Oncology Biol. Phys.; Vol. 10, pp. 747-751 (1984) again utilized absorbable materials and Iodine-125 seeds to perform a permanent planer radioactive implant. This technique utilizes commercially available absorbable polymer mesh and putty material. At the time the surgical debulking of tumor, the mesh is cut to conform to the tumor bed, the putty is flattened into pancake fashion, and the seeds are placed into the putty, at a predetermined spacing then placed on the mesh which is sutured over the tumor bearing surface. Although this solves the problem of planar implants over denuded areas, and reduces actual suturing time, new problems are created. First, since the pancake style implant can only be manufactured after the tumor is removed and the shape of the tumor bed is known, and since it has to be manufactured under sterile conditions, the end result is a greatly extended operating time while the pancake is being prepared. Another problem is there is no quality assurance of the thickness of the pancake holding the radioactive seeds, and thus in thin areas the material will be absorbed quickly resulting in premature release of the seeds, underdose in that area, and recurrence of tumor.
It is also noted in the techniques of Hilaris and Martinez above that the seeds are low dose rate, and would not be applicable in a rapidly proliferating tumor system.
Accordingly, among the objectives of the present invention are to provide a delivery system for temporary radiation therapy which obviates the aforementioned disadvantages and holds the seeds in accurate position to provide the desired radiation therapy.
In accordance with the invention, the delivery system comprises a carrier in the form of a sheet of absorbable material which has a plurality of passages. The sheet is sutured adjacent the area to be treated and a catheter is inserted in each passage. A tube containing a plurality of radioactive seeds is inserted in each catheter. After the desired treatment, the tubes and catheters are removed leaving the carrier in the body.


An adhesive suitable for use in the oral environment is provided. The adhesive comprises a filler, hardenable resin, a hardener, and a colorant, the composition has an initial color prior to exposure to actinic radiation and a final color that is different from the initial color subsequent to the composition being exposed to actinic radiation. The adhesive can be precoated on to orthodontic appliances.

The present invention relates adhesive suitable for use in the oral environment, such as a patient""s mouth. In particular, the adhesive has a vibrant initial color and having the capability of changing to a final color upon exposure to actinic radiation. The initial and final colors are different.
Orthodontic treatment involves movement of malpositioned teeth to orthodontically correct positions. Tiny orthodontic appliances, known as brackets, are connected to anterior, cuspid and bicuspid teeth, and an archwire forms a track to guide movement of the teeth to desired positions. In previous years, the orthodontic appliances were connected to teeth by welding or brazing each appliance to a metal band, which was then placed on the desired tooth. But, more recently, it has been preferred to bond the brackets directly to the tooth surface. The direct bonding method minimized the use of metal band thus eliminating the xe2x80x9cmetallic mouthxe2x80x9d appearance that is often associated with orthodontic treatment.
The use of a bonding method can typically require, among other steps, placing an amount of adhesive on the bracket, applying the brackets to the desired, preferably preconditioned teeth, and removing excess adhesive. Conventional orthodontic adhesives are typically clear or contain pigment, which gives the adhesives a white or tooth color. It is desirable that a sufficient but not an excess amount of adhesive is used to bond the brackets to the teeth surface. Excess adhesive on the teeth will eventually be a site for bacteria accumulation. Because orthodontic treatment can last from 18 to 36 months, the bacteria accumulation may damage the teeth and may lead to discoloration of the adhesive, both of which are very undesirable. Removal of the excess adhesive from teeth surfaces can be difficult if there is similarity in the adhesive color and the teeth color, i.e., due to a lack of a contrasting color in the adhesive.
Some skilled in the art have explored the use of color changing adhesive, in particular for orthodontic applications. For example, an orthodontic adhesive having color changing capabilities upon curing by a light source is commercially available from the Orec(copyright) Corporation, San Marcos, Calif. The company supplies a product identified as CRYPSIS Color Change Orthodontic Bonding Adhesive (Photocure). As of the filing date, the adhesive is described at Orec""s web site (www.orec.com/Pg21.htm) as having an initial yellow color, which allows easy visualization and removal of excess adhesive prior to curing. Once cured, the adhesive turns to tooth-like color.
U.S. Pat. No. 5,545,676 (Palazzotto et al.) discloses a composition useful as a photocurable adhesive, e.g., for orthodontics. The composition comprises (a) free-radically polymerizable monomer and (b) photoinitiator system, soluble in the monomer, comprising photochemically effective amounts of (i) diaryliodonium salt (xe2x80x9ciodonium saltxe2x80x9d), (ii) sensitizing compound (xe2x80x9csensitizerxe2x80x9d) capable of absorbing light within the range of wavelengths between about 300 and 1000 nanometers and capable of sensitizing 2-methyl-4,6-bis-(tricholormethyl)-s-triazine, and (iii) electron donor compound. The donor is different from the sensitizer. It is further specified that the donor oxidation potential is 0 less than Eox(donor)xe2x89xa6Eox(p-dimethoxybenzene). Although the patent describes a very useful photoinitiator system, it does not disclose a system or a composition that has color changing capabilities.
A need remains for adhesives that exhibits effective color changing capabilities within a practical working time to aid a dental practitioner in applying orthodontic appliances to a patient""s teeth.
The present invention provides a new adhesive suitable for use in the oral environment. The adhesive is used in orthodontic application. It contains a colorant and optionally a sensitizer to impart color-changing capability. The adhesive provides a vibrant initial color (before actinic radiation exposure) that is remarkably different than dental structures, such as teeth, thereby aiding the practitioner in using a sufficient amount and in placing it in and on areas of the dental structure. Useful initial colors include pink, red, blue, orange, and green, which tends to provide better color contrast against the dental structures, as compared to a yellow colored adhesive. Methods of making and using the color-changing adhesive are also provided.
In brief summary, the present invention is directed to an adhesive for use in the oral environment, the adhesive comprising a filler, a hardenable resin, a hardener, and a colorant, the adhesive having an initial color prior to exposure to actinic radiation and a final color after exposure to actinic radiation. The initial and final colors are different. The inventive adhesive is capable of undergoing a change in color of xcex94E* greater than about 10 as a result of actinic radiation exposure. In one inventive embodiment, a dye or a combination of dyes can be used to impart a desired initial color.
Advantageously, the adhesive""s final color preferably closely matches the dental structures that surrounds it. Alternatively, it is able to transmit the color of the underlying dental structure, i.e., the final color is substantially clear. By formulating the adhesive so that it results in a tooth-like hue, the adhesive can form an xe2x80x9caestheticxe2x80x9d layer upon the tooth surface. Dental materials that match normal tooth color and shades (i.e. tooth-like) are often considered to have high aesthetic quality, especially when the dental material is indistinguishable from the normal tooth surface when viewed from only a short distance.
Another advantage of the present invention is ease of use because the adhesive cures quickly. A practitioner such as an orthodontist can easily cure it using a conventional dental curing light.
The present invention also provides for orthodontic appliances that are precoated with the adhesive, the appliance packaged conveniently in capsule-like containers. The precoated appliance typically has a precise amount of adhesive on its base. Precoated appliances represent a significant advantage to the orthodontists. For example, when it is desired to mount the appliance on a tooth, the appliance is simply removed from the package and directly placed on the tooth surface. There is little need, if any, to remove excess adhesive.
The packaging components used to store the adhesive and precoated orthodontic appliances preferably minimize, if not nearly eliminate, the transmission of visible and near infrared light to the appliances. In this way, the stability of the adhesive, and thus the orthodontic appliance can be maintained for a long period of time, on the order of years.
As used herein the following terms are intended to have the following definitions:
xe2x80x9caesthetic layerxe2x80x9d, means a layer that is customarily positioned in a visible location on teeth (e.g., the tops of molars, labial surfaces of incisors and cuspids) and is either visible due to the layer being the outermost layer or can be seen through any overlying layer;
xe2x80x9chardenablexe2x80x9d is descriptive of a material that can be cured or solidified e.g., by heating to remove solvent, heating to cause polymerization, chemical cross-linking, radiation-induced polymerization or crosslinking, or the like;
xe2x80x9cphoto-bleach(able)xe2x80x9d means a loss of color upon exposure to actinic radiation;
xe2x80x9chardenerxe2x80x9d means a system that initiates hardening of a resin, and can be used synonymously with xe2x80x9cinitiator systemxe2x80x9d;
xe2x80x9corthodontic appliancexe2x80x9d means any device intended to be bonded to the teeth, including, but not limited to, orthodontic brackets, buccal tubes, lingual buttons, and cleats. The appliance has a base for receiving adhesive and it can be made of metal, plastic, ceramic, and combinations thereof; and
xe2x80x9ctooth-likexe2x80x9d color refers to the broad range of colors and shades of naturally occurring teeth, which can be quantified for example, using the Vita(trademark)-shade system (covering the range A1 through D4), a tooth color/shade guide frequently used by dental practitioners.
Because the adhesive is used in the oral environment, it must be non-toxic and not irritate soft tissues, such as the gums, tongue, and cheek. It has a vibrant initial color to provide strong color contrast between it and the teeth. The color difference between the tooth color and the initial adhesive color, in terms of xcex94E*, should be at least greater than 40, preferably greater than 45, more preferably greater than 50, and most preferably greater than 55, when the tooth color is set at B1 using the Vita(trademark)-shade system.
The adhesive is cured using an actinic light source. The cure time is less than about 60 seconds, preferably less than about 45 seconds, and more preferably, less than about 30 seconds. The adhesive photobleaches. It should not, however, bleach substantially while the orthodontist is working with it under the normal office conditions, i.e., normal lighting, room temperature of about 22xc2x0 to 26xc2x0 C., and normal relative humidity of about 35% to 65%. In other words, the adhesive should retain nearly all (at least 80%, preferably 90% as measured using a colorimeter) of its initial color while the orthodontist prepares it. A typical working time could be anywhere from about 5 to 15 minutes per tooth. In the case of precoated orthodontic appliances, the working time would be less than about 5 minutes per tooth.
Each of the adhesive components is described in detail below, as well as the method of making and using the adhesive, and precoated orthodontic appliances.
The amount of filler used, referred to herein as the xe2x80x9cloading levelxe2x80x9d and expressed as a weight percent based on the total weight of the adhesive, will vary depending on the type of filler, the hardenable resin and other adhesive components. Preferably, the filler is present from about 65% to 85%, more preferably from about 70% to 80% by weight based on the total weight of the adhesive.
Fillers may be selected from one or more of any material(s) suitable for use in medical applications, such as fillers currently used in dental restorative compositions and the like. Preferably the filler is finely divided and has a maximum particle diameter of less than about 50 micrometers and an average particle diameter of less than about 10 micrometers. The filler can have a unimodal or polymodal (e.g., bimodal) particle size distribution. The filler can be an inorganic material. It can also be a crosslinked organic material that is insoluble in the hardenable resin, and is optionally filled with inorganic filler. The filler can be radiopaque, radiolucent or nonradiopaque.
Examples of suitable organic filler particles include filled or unfilled pulverized polycarbonates, polyepoxides, and the like.
Examples of suitable inorganic fillers are naturally-occurring or synthetic materials such as quartz, nitrides (e.g., silicon nitride), glasses derived from, for example, Ce, Sb, Sn, Zr, Sr, Ba, and Al, colloidal silica, feldspar, borosilicate glass, kaolin, talc, titania, and zinc glass; low Mohs hardness fillers such as those described in U.S. Pat. No. 4,695,251; and submicron silica particles (e.g., pyrogenic silicas such as the xe2x80x9cAerosilxe2x80x9d Series xe2x80x9cOX 50xe2x80x9d, xe2x80x9c130xe2x80x9d, xe2x80x9c150xe2x80x9d and xe2x80x9c200xe2x80x9dsilicas sold by DeGussa and xe2x80x9cCab-O-Sil M5xe2x80x9d silica sold by Cabot Corp.).
Preferred filler particles are quartz, submicron silica, and non-vitreous microparticles of the type described in U.S. Pat. No. 4,503,169. Metallic fillers may also be used, such as particulate metal filler made from a pure metal, such as those of Groups IVA, VA, VIA, VIIA, VIII, IIB, or IIB, aluminum, indium, and thallium of Group IIB, and tin and lead of Group IVB, or alloys thereof. Conventional dental amalgam alloy powders, which are typically mixtures of silver, tin, copper, and zinc, can optionally be used. The particulate metallic filler preferably has an average particle size of about 1 to 100 micrometers, more preferably about 1 to 50 micrometers. Mixtures of these fillers are also contemplated, as well as combination fillers made from organic and inorganic materials. Fluoroaluminosilicate glass fillers, either untreated or silanol treated, can be used. These glass fillers have the added benefit of releasing fluoride at the site of dental work when placed in the oral environment.
Optionally, the surface of the filler particles may be treated with a surface treatment, such as a coupling agent, in order to enhance the bond between the filler and the hardenable resin. The coupling agent may be functionalized with reactive curing groups, such as acrylates, methacrylates, epoxies, and the like. Examples of coupling agents include silanes, such as gamma-methacryloxypropyltrimethoxy-silane, gamma-mercaptopropyltriethoxysilane, beta-(3,4-epoxycyclohexyl)-ethyltrimethoxysilane, gamma-glycidoxypropyltrimethoxysilane, and the like.
The inventive adhesive has an initial color remarkably different than the dental structures. Color is imparted to the adhesive through the use of a colorant. Preferably, the colorant is a dye. In some embodiments, the sensitizer, a component of the initiator system may provide some color to the adhesive. The sensitizer, however, is not relied solely as the colorant, i.e., it alone is not used to impart a vibrant initial color to the adhesive. Thus, in some embodiments the sensitizer may serve a dual purpose of providing photoactivation and imparting a color to the adhesive.
The colorant makes up about 0.001% but less than about 1%, preferably about 0.01% to 0.1% by weight of the total adhesive weight. The amount of colorant may vary depending on its extinction coefficient, the ability of the human eye to discern the initial color, and the desired color change.
A dye may be a pigment and therefore includes any types of suitable pigments. The colorants should be added in an effective amount to achieve the desired color. For health reasons, food, drug, and cosmetic grade dyes are preferred. At least one of the dyes in the inventive adhesive is reactive or photo-bleachable, in order for the final color to be distinguishable from the initial color. Additional dyes that may or may not be reactive or photo-bleachable can be used to achieve a desired color. Thus, a non-reactive dye may impart a certain color or shade when mixed with a reactive dye to achieve a desired initial color.
The color formation and bleaching characteristics of the photo-bleachable dye varies depending on a variety of factors such as, e.g., acid strength, dielectric constant, polarity, amount of oxygen, and moisture content in the atmosphere. But, the bleaching properties of the dye can be readily determined by irradiating the adhesive and evaluating the change in color. Preferably, at least one colorant is at least partially soluble in the hardenable resin.
Suitable colorants that can impart color to the inventive adhesive include, e.g., methylene blue, amaranth, erythrocin, floxine, rose bengal, acid red, Tartrazine, Sunset Yellow FCF, Fast Green FCF, Brilliant Blue FCF, indigo carmine, phenolphthalain, sulfophthalain, Yale Violet, methyl orange, fluorescene, methyl viologene, indophenol, dimurosbetaine, bromeosin Y, laudamine B, thionine, neutral red, toluidine blue O, indocyanine green, sulfobromophthalain, uranin, lithol rubin B, lake red C, lithol red, tetrachlorotetrabrom fluorescene, brilliant lake red R, deep maroon, toluidine red, tetrabrom fluorescene, fast acid magenta, permanent red, dibromfluorescene, permanent orange, uranine, quinone yellow, WS, alizarin cyanine green F, quinizarine green SS, light green SF yellow, patent blue NA, carbathrene blue, resorcinol brown, alizarin purple SS, brilliant fast scarlet, permanent red F5R, Ponceaux SX, fast red S, oil orange SS, poral yellow 5G, fast light yellow 3G, naphthol green B, Ginea Green B, Sudan Blue B, alizarol purple, naphthol blue black, crocin, crocin blue, orange paprica, chlorophyl, cartamine, safflower yellow, beet red, direct fast yellow GC, direct fast orange, direct fast scarlet 4BS, fast red 6BLL, direct sky blue 5B, direct fast turquoise blue GL, direct copper blue 2B, coprantine green G, direct fast black D, milling yellow O, acid brilliant scarlet 3R, acid violet 5B, azaline direct blue A2G, acid cyanine 6B, acid cyanine SR, acid cyanine green G, milling brown 3G, acid fast black VLG, acid black WA, cation yellow 3G, cation golden yellow GL, cation flavin 10G, cation yellow 5GL, cation orange R, cation brown 3GL, cation pin FG, cation brilliant red 4G, cation red GTL, cation red BLH, cation red 6B, cation red 5B, cation blue GLH, cation navy blue RHL, alizarine, chrome fast blue MB, chrome fast brown KE, chrome black P2B, chrome black T, fast scarlet G base, naphthol AS, naphthol AS-G, vat yellow GCN, vat orange RRTS, indigo, vat blue RSN, vat blue BC, vat brilliant green FFB, vat olive green B, vat olive T, vat brown R, vat gray M, disperse fast yellow G, disperse pink RF, disperse blue FFR, disperse blue green B, disperse yellow 5G, disperse golden yellow GG, disperse yellow RL, disperse yellow 3G, disperse orange B, disperse yellow brown 2R, disperse fast ruby 3B, disperse fast red FB, disperse red FL, disperse red GFL, disperse brilliant pink REL, disperse violet HFRL, disperse blue FB, disperse turquoise blue GL, disperse navy blue 2GL, disperse developer, fluorescent brightener WG, fluorescent brightener ERN, fluorescent brightener AT, fluorescent brighter SA, solvent orange G, solvent fast yellow 3RE, solvent fast red B, solvent fast blue HFL, reactive yellow 3G, reactive orange 2R, reactive red 3B, reactive scarlet 2G, reactive blue 3G, reactive blue R, reactive blue BR, reactive turquoise GF, reactive brilliant blue R, reactive black B, fast yellow G, fast yellow 10G, disazo yellow AAA, disazo yellow AAMX, flavane yellow, chromophthal yellow GR, methine yellow GR, methine yellow, sunset yellow lake, anthrapyrimidine yellow, isoindolinone yellow R, quinophthalone yellow, dinitroaniline orange, pyrazolone orange, dianidine orange, persian orange lake, benzimidazolone orange HL, perynone orange, pyranthrone orange, parared, naphthol red FRR, toluidine red, naphthol carmine FB, naphthol red M, naphthol red BS, naphthol red RN, pyrazolone red, permanent red 2B, lithol red, bon lake red C, lake red C, brilliant carmin 6B, brilliant cannin 3B, Bordeaux 10B, von maroon M, brilliant scarlet G, rhodamine 6G lake, mudder lake, thioindigo Bordeaux, naphthol red FGR, brilliant carmin BS, quinacridone magenta, perylene vermillian, naphthol carmin FBB, perylene red BL, chromophthal scarlet, anthrone red, naphthol red F5RK, erythrocin lake, dianthraquinolyl red, perylene red, perylene maroon, benzimidazolone carmin HF4C, perylene scarlet, amaranth lake, quinacridone red E, pyranthron red, rhodamine B lake, methyl violet lake, alizarine maroon lake, quinacridone red, dioxadine violet, thioindigo magenta, Victoria blue lake, Victoria blue 6G lake, phthalocyanine blue, alkali blue G, indanthrone blue, brilliant green lake, malachite green lake, phthalocyanine green, pigment green B, phthalocyanine green 6Y, benzimidazolone brown HFR, aniline black, dialilide yellow H10G, dialilide yellow HR, carbazole violet, metacresol purple, bromophenol blue, crystal violet, gentiana violet, bromocresol green, bromothimol blue, etc. can be mentioned.
Particularly preferred dyes include Rose Bengal, Methylene Violet, Methylene Blue, Fluorescein, Eosin Yellow, Eosin Y, Ethyl Eosin, Eosin bluish, Eosin B, Erythrosin B, Erythrosin Yellowish Blend, Toluidine Blue, 4xe2x80x2,5xe2x80x2-Dibromofluorescein and blends thereof. The color of the inventive adhesive may be additionally imparted by a sensitizing compound.
The color change in the inventive adhesive is initiated by light. Preferably the adhesive""s color change is initiated using actinic radiation, using, e.g., a dental curing light which emits visible or near infrared (IR) light for a sufficient amount of time. The mechanism that initiates the color change in the compositions of the invention may be separate from or substantially simultaneous with the curing mechanism that hardens the resin. Thus, e.g., an adhesive may cure (harden) when polymerization is initiated chemically (redox) or thermally, and the color change from an initial color to a final color may occur subsequent to the hardening process upon exposure to actinic radiation.
The change in adhesive color from its initial color to a final color is preferably quantified by a Color Test as described below. Using the Color Test, a value of xcex94E* is determined, which indicates the total color change in a 3-dimensional color space. The human eye can detect a color change of approximately 3 xcex94E* units in normal lighting conditions. The dental compositions of the present invention are preferably capable of having a color change, xcex94E*, of greater than about 20; more preferably, xcex94E* is greater than about 30; most preferably xcex94E* is greater than about 40.
The inventive orthodontic adhesives include a hardenable resin. The adhesive comprises about 10% to 40%, preferably 15% to 35%, more preferably 20% to 30% of the hardenable resin. The resin, in the presence of a hardener, is capable of being hardened to form a polymer network such as, e.g., acrylate resins, methacrylate resins, or mixtures thereof. Preferably, the hardenable resin is made from one or more matrix-forming oligomer, monomer, or polymer, or blend thereof.
The hardenable resin should be suitable for use in the oral environment, i.e., non-toxic. Preferably, the resin is made from an organic resin having sufficient strength and hydrolytic stability.
Examples of suitable resins include acrylate, methacrylate, urethane, and carbamoylisocyanurate resins, e.g., those shown in U.S. Pat. Nos. 3,066,112; 3,539,533; 3,629,187; 3,709,866; 3,751,399; 3,766,132; 3,860,556; 4,002,669; 4,115,346; 4,259,117; 4,292,029; 4,308,190; 4,327,014; 4,379,695; 4,387,240 and 4,404,150, and mixtures and derivatives thereof.
One class of preferred hardenable resins is materials having free radically active functional groups and include monomers, oligomers, and polymers having one or more ethylenically unsaturated groups. Alternatively, the hardenable resin can be a material from the class of resins that include cationically active functional groups. In another alternative, a mixture of hardenable resins that include both cationically curable and free radically curable groups may be used.
In the class of hardenable resins having free radically active functional groups, suitable materials for use in the invention contain at least one ethylenically unsaturated bond, and are capable of undergoing addition polymerization. Such free radically polymerizable materials include mono-, di- or poly-acrylates and methacrylates such as methyl acrylate, methyl methacrylate, ethyl acrylate, isopropyl methacrylate, n-hexyl acrylate, stearyl acrylate, allyl acrylate, glycerol diacrylate, glycerol triacrylate, ethyleneglycol diacrylate, diethyleneglycol diacrylate, triethyleneglycol dimethacrylate, 1,3-propanediol diacrylate, 1,3-propanediol dimethacrylate, trimethylolpropane triacrylate, 1,2,4-butanetriol trimethacrylate, 1,4-cyclohexanediol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, sorbitol hexacrylate, the diglycidyl methacrylate of bis-phenol A (xe2x80x9cBis-GMAxe2x80x9d), bis[1-(2-acryloxy)]-p-ethoxyphenyldimethylmethane, bis[1-(3-acryloxy-2-hydroxy)]-p-propoxyphenyldimethylmethane, and trishydroxyethyl-isocyanurate trimethacrylate; the bis-acrylates and bis-methacrylates of polyethylene glycols of molecular weight 200-500, copolymerizable mixtures of acrylated monomers such as those in U.S. Pat. No. 4,652,274, and acrylated oligomers such as those of U.S. Pat. No. 4,642,126; and vinyl compounds such as styrene, diallyl phthalate, divinyl succinate, divinyl adipate and divinylphthalate. Mixtures of two or more of these free radically polymerizable materials can be used if desired.
For free radical polymerization (curing), an initiation system or hardener can be selected from systems that initiate polymerization via radiation, heat, or redox/auto-cure chemical reaction. A class of initiators capable of initiating polymerization of free radically active functional groups includes free radical-generating photoinitiators, optionally combined with a photosensitizer or accelerator. Such initiators typically can be capable of generating free radicals for addition polymerization upon exposure to light energy having a wavelength between 200 and 1200 nm.
A variety of visible or near-IR photoinitiator systems may be used for photopolymerization of free-radically polymerizable materials useful in the invention. For example, in free radical polymerization (curing), a photoinitiation system can be selected from systems which initiate polymerization via a two component system of an amine and an xcex1-diketone as described in U.S. Pat. No. 4,071,424, which is herein incorporated by reference. Alternatively and preferably, the resin can be combined with a three component or ternary photoinitiator system such as described in U.S. Pat. No. 5,545,676. A preferred initiator system comprises a sensitizer (which may or may not impart color) and an electron donor. Optionally the initiator system may further comprise an onium salt, thus making the initiator system a ternary system.
The three components of a photoinitiator system are present in the compositions of the invention in xe2x80x9cphotochemically effective amountsxe2x80x9d; that is, amounts of each component sufficient to enable the monomer to undergo photochemical gelation or curing upon exposure to light of the desired wavelength.
In the ternary photoiniator system, the first component is an iodonium salt, e.g., a diaryliodonium salt. The iodonium salt is preferably soluble in the monomer and shelf-stable (i.e., does not spontaneously promote polymerization) when dissolved therein in the presence of the sensitizer and donor. Accordingly, selection of a particular iodonium salt may depend to some extent upon the particular monomer, polymer or oligomer, sensitizer and donor chosen. Suitable iodonium salts are described in U.S. Pat. Nos. 3,729,313, 3,741,769, 3,808,006, 4,250,053 and 4,394,403. The iodonium salt can be a simple salt (e.g., containing an anion such as Clxe2x88x92, Brxe2x88x92, Ixe2x88x92 or C4 H5 SO3xe2x88x92) or a metal complex salt (e.g., containing SbF5 OHxe2x88x92 or AsF6xe2x88x92). Mixtures of iodonium salts can be used if desired. Preferred iodonium salts include diphenyliodonium salts such as diphenyliodonium chloride, diphenyliodonium hexafluorophosphate, and diphenyliodonium tetrafluoroborate.
The second component in a ternary photoinitiator system is a sensitizer. Preferably, the sensitizer is soluble in the monomer, and is capable of light absorption somewhere within the range of wavelengths of greater than 400 to about 1200 nanometers, more preferably greater than 400 to about 700 nanometers and most preferably greater than 400 to about 600 nanometers. The sensitizer may also be capable of sensitizing 2-methyl-4,6-bis(trichloromethyl)-s-triazine, using the test procedure described in U.S. Pat. No. 3,729,313. Preferably, in addition to passing this test, a sensitizer is also selected based in part upon shelf stability considerations. Accordingly, selection of a particular sensitizer may depend to some extent upon the particular monomer, oligomer or polymer, the iodonium salt, and the donor chosen.
The sensitizer may also impart a photobleachable color in addition to the color imparted by the dye or pigment colorant. For example, camphorquinone can impart a yellow color to the materials of the invention and Rose Bengal can impart a reddish color to the materials.
Suitable sensitizers can include compounds in the following categories: ketones, coumarin dyes (e.g., ketocoumarins), xanthene dyes, fluorone acridine dyes, thiazole dyes, thiazine dyes, oxazine dyes, azine dyes, aminoketone dyes, porphyrins, aromatic polycyclic hydrocarbons, p-substituted aminostyryl ketone compounds, aminotriaryl methanes, merocyanines, squarylium dyes, and pyridinium dyes. Xanthene dyes include those dyes whose molecular structure is related to xanthene and have a Color Index number ranging from 45000-45999. Ketones (e.g., monoketones or alpha-diketones), ketocoumarins, aminoarylketones and p-substituted aminostyryl ketone compounds are preferred sensitizers. For applications requiring high sensitivity, it is preferred to use a sensitizer containing a julolidinyl moiety. For applications requiring deep cure (e.g., cure of highly-filled composites), it is preferred to use sensitizers having an extinction coefficient below about 1000, more preferably below about 100, at the desired wavelength of irradiation for photopolymerization. Alternatively, dyes that exhibit reduction in light absorption or photobleaching at the excitation wavelength upon irradiation can be used.
For example, a preferred class of ketone sensitizers has the formula:
ACO(X)bB
where X is CO or CR5 R6, where R5and R6 can be the same or different, and can be hydrogen, alkyl, alkaryl or aralkyl, b is zero or one, and A and B can be the same or different and can be substituted (having one or more non-interfering substituents) or unsubstituted aryl, alkyl, alkaryl, or aralkyl groups, or together A and B can form a cyclic structure which can be a substituted or unsubstituted cycloaliphatic, aromatic, heteroaromatic or fused aromatic ring.
Suitable ketones of the above formula include monoketones (b=0) such as 2,2-, 4,4- or 2,4-dihydroxybenzophenone, di-2-pyridyl ketone, di-2-furanyl ketone, di-2-thiophenyl ketone, benzoin, fluorenone, chalcone, Michler""s ketone, 2-fluoro-9-fluorenone, 2-chlorothioxanthone, acetophenone, benzophenone, 1- or 2-acetonaphthone, 9-acetylanthracene, 2-, 3- or 9-acetylphenanthrene, 4-acetylbiphenyl, propiophenone, n-butyrophenone, valerophenone, 2-, 3- or 4-acetylpyridine, 3-acetylcoumarin and the like. Suitable diketones include aralkyldiketones such as anthraquinone, phenanthrenequinone, o-, m- and p-diacetylbenzene, 1,3-, 1,4-, 1,5-, 1,6-, 1,7- and 1,8-diacetylnaphthalene, 1,5-, 1,8- and 9,10-diacetylanthracene, and the like. Suitable alpha-diketones (b=1 and Xxe2x95x90CO) include 2,3-butanedione, 2,3-pentanedione, 2,3-hexanedione, 3,4-hexanedione, 2,3-heptanedione, 3,4-heptanedione, 2,3-octanedione, 4,5-octanedione, benzil, 2,2xe2x80x2-3 3xe2x80x2- and 4,4xe2x80x2-dihydroxylbenzil, furil, di-3,3xe2x80x2-indolylethanedione, 2,3-bornanedione (camphorquinone), biacetyl, 1,2-cyclohexanedione, 1,2-naphthaquinone, acenaphthaquinone, and the like.
The third component of a ternary initiator system is a donor. Preferred donors include, e.g., amines (including aminoaldehydes and aminosilanes), amides (including phosphoramides), ethers (including thioethers), ureas (including thioureas), ferrocene, sulfinic acids and their salts, salts of ferrocyanide, ascorbic acid and its salts, dithiocarbamic acid and its salts, salts of xanthates, salts of ethylene diamine tetraacetic acid and salts of tetraphenylboronic acid. The donor can be unsubstituted or substituted with one or more non-interfering substituents. Particularly preferred donors contain an electron donor atom such as a nitrogen, oxygen, phosphorus, or sulfur atom, and an abstractable hydrogen atom bonded to a carbon or silicon atom alpha to the electron donor atom. A wide variety of donors is disclosed in U.S. Pat. No. 5,545,676.
Alternatively, free-radical initiators useful in the invention include the class of acylphosphine oxides, as described in European Patent Application No. 173567, U.S. Pat. No. 4,737,593 and United Kingdom Patent. No. GB 2,310,855. Such acylphosphine oxides are of the general formula
(R9)2xe2x80x94P(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94R10
wherein each R9 individually can be a hydrocarbyl group such as alkyl, cycloalkyl, aryl, and aralkyl, any of which can be substituted with a halo-, alkyl- or alkoxy-group, or the two R9 groups can be joined to form a ring along with the phosphorous atom, and wherein R10 is a hydrocarbyl group, an S-, O-, or N-containing five- or six-membered heterocyclic group, or a xe2x80x94Zxe2x80x94C(xe2x95x90O)xe2x80x94P(xe2x95x90O)xe2x80x94(R9)2 group, wherein Z represents a divalent hydrocarbyl group such as alkylene or phenylene having from 2 to 6 carbon atoms.
Preferred acylphosphine oxides useful in the invention are those in which the R9 and R10 groups are phenyl or lower alkyl- or lower alkoxy-substituted phenyl. The terms xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d mean such groups having from 1 to 4 carbon atoms. Most preferably, the acylphosphine oxide is bis(2,4,6-trimethylbenzoyl)phenyl phosphine oxide (IRGACURE(trademark) 819, available from Ciba Specialty Chemicals, Tarrytown, N.Y.).
Tertiary amine reducing agents may be used in combination with an acylphosphine oxide. Illustrative tertiary amines useful in the invention include ethyl 4-(N,N-dimethylamino)benzoate and N,N-dimethylaminoethyl methacrylate. The initiator can be used in catalytically-effective amounts, such as from about 0.1 to 5 weight percent, based on the weight of ethylenically-unsaturated compound present, of the acylphosphine oxide plus from about 0.1 to about 5 weight percent, based on the weight of ethylenically-unsaturated compound present, of the tertiary amine.
Commercially-available phosphine oxide photoinitiators capable of free-radical initiation when irradiated at wavelengths of greater than 400 nm to about 1200 nanometer include a 25:75 mixture, by weight, of bis(2,6-dimethoxybenzoyl)-2,4,4-trimethylpentyl phosphine oxide and 2-hydroxy-2-methyl-1-phenylpropan-1-one (IRGACURE(trademark) 1700, Ciba Specialty Chemicals), 2-benzyl-2-(N,N-dimethylamino)-1-(4-morpholinophenyl)-1-butanone (IRGACURE(trademark) 369, Ciba Specialty Chemicals), bis(xcex75-2,4-cyclopentadien-1-yl)-bis(2,6-difluoro-3-(1H-pyrrol-1-yl)phenyl) titanium (IRGACURE(trademark) 784 DC, Ciba Specialty Chemicals), a 1:1 mixture, by weight, of bis(2,4,6-trimethylbenzoyl)phenyl phosphine oxide and 2-hydroxy-2-methyl-1-phenylpropane-1-one (DAROCUR(trademark) 4265, Ciba Specialty Chemicals), and ethyl-2,4,6-trimethylbenzylphenyl phosphinate (LUCIRIN(trademark) LR8893X, BASF Corp., Charlotte, N.C.).
Another free-radical initiator system that can alternatively be used in the inventive adhesive includes the class of ionic dyexe2x80x94counterion complex initiators comprising a borate anion and a complementary cationic dye. Borate salt photoinitiators are described, for example, in U.S. Pat. Nos. 4,772,530, 4,954,414, 4,874,450, 5,055,372, and 5,057,393. A borate salt photoinitiator may also use photobleachable sensitizing colorants.
Borate anions useful in these photoinitiators generally can be of the formula:
R1R2R3R4Bxe2x88x92
wherein R1, R2, R3, and R4 independently can be alkyl, aryl, alkaryl, allyl, aralkyl, alkenyl, alkynyl, alicyclic and saturated or unsaturated heterocyclic groups. Preferably, R2, R3, and R4 are aryl groups and more preferably phenyl groups, and R1 is an alkyl group and more preferably a secondary alkyl group.
Cationic counterions can be cationic dyes, quaternary ammonium groups, transition metal coordination complexes, and the like. Cationic dyes useful as counterions can be cationic methine, polymethine, triarylmethine, indoline, thiazine, xanthene, oxazine or acridine dyes. More specifically, the dyes may be cationic cyanine, carbocyanine, hemicyanine, rhodamine, and azomethine dyes. Specific examples of useful cationic dyes include Methylene Blue, Safranine O, and Malachite Green. Quaternary ammonium groups useful as counterions can be trimethylcetylammonium, cetylpyridinium, and tetramethylammonium. Other organophilic cations can include pyridinium, phosphonium, and sulfonium. Photosensitive transition metal coordination complexes that may be used include complexes of cobalt, ruthenium, osmium, zinc, iron, and iridium with ligands such as pyridine, 2,2xe2x80x2-bipyridine, 4,4xe2x80x2-dimethyl-2,2xe2x80x2-bipyridine, 1,10-phenanthroline, 3,4,7,8-tetramethylphenanthroline, 2,4,6-tri(2-pyridyl-s-triazine) and related ligands.
Yet another alternative class of initiators capable of initiating polymerization of free radically active functional groups includes conventional chemical initiator systems such as a combination of a peroxide and an amine. These initiators, which rely upon a thermal redox reaction, are often referred to as xe2x80x9cauto-cure initiators.xe2x80x9d They are typically supplied as two-part systems in which the reactants are stored apart from each other and then combined immediately prior to use.
In a further alternative, heat or thermal energy may be used to initiate the curing, or polymerization, of free radically active groups in the presence of free radical-generating thermal initiators. Examples include peroxides such as, for example, benzoyl peroxide and lauryl peroxide, and azo compounds such as, for example, 2,2-azobis-isobutyronitrile (AIBN). Examples of heat sources suitable for the dental materials of the invention include inductive, convective, and radiant. Thermal sources should be capable of generating temperatures of at least 40xc2x0 C. to 150xc2x0 C. under normal conditions or at elevated pressure. This procedure is preferred for initiating polymerization of materials occurring outside of the oral environment.
The initiator compounds are preferably provided in the inventive adhesive in an amount effective to initiate or enhance the rate of cure of the resin system. Photopolymerizable compositions useful in the invention are prepared by simply admixing, under xe2x80x9csafe lightxe2x80x9d conditions, the components as described above. Suitable inert solvents may be used, if desired, when effecting this mixture. Any solvent may be used that does not react appreciably with the adhesive components. Examples of suitable solvents include acetone, dichloromethane, and acetonitrile. A liquid material to be polymerized may be used as a solvent for another liquid or solid material to be polymerized.
The inventive adhesive may optionally comprise additional adjuvants suitable for use in the oral environment, including flavorants, anti-microbials, fragrance, stabilizers, viscosity modifiers, rheology modifiers, fillers and fluoride releasing materials. For example, a fluoride releasing glass may be added to the materials of the invention to provide the benefit of long-term release of fluoride. Fluoroaluminosilicate glasses are suitable for the invention, such as a silanol treated fluoroaluminosilicate glass fillers, as described in U.S. Pat. No. 5,332,429. Organic fluoride sources are also suitable for the invention, such as those described in U.S. Pat. No. 4,871,786. Other suitable adjuvants include agents that impart fluorescence and/or opalescence.
The adhesive can be made by first mixing the hardenable resin with the hardener and colorants. The filler, which was made by conventional processes, is then added. Typically, the entire mixing process is done under conditions that minimize the exposure of the components to visible and infrared light.
A method of making precoated orthodontic appliance of this invention is described in U.S. Pat. No. 5,552,177 (Jacobs et al.). That patent discloses a method for applying adhesive to a base of an orthodontic appliance comprising the following steps: (a) placing a quantity of adhesive onto a carrier; (b) cooling at least a portion of the adhesive to a temperature below ambient, (c) contacting the base of the appliance with the adhesive; and (d) disengaging the adhesive from the carrier while the temperature of the portion of the adhesive is below ambient. It is further disclosed that cooling at least a portion of the adhesive facilitates automated handling of the adhesive and enhances trimming away excess adhesive to leave a precise quantity on the appliance. In this way, the dental practitioner spends minimal time and labor, if any, during installation of the appliance to the patient""s teeth. The patent also discloses useful packaging materials that contain a plurality of wells in a substrate. The wells are of suitable size and dimensions to hold the appliances. After the wells are filled with the appropriate number of appliances, a lid is used to cover the wells. Suitable lid materials include, e.g., polyester, metallized films, foils, and film laminates. The entire packaging material should provide barriers to the transmission of light, water vapor, and oxygen. U.S. Pat. Nos. 5,015,180; 5,172,809; 5,354,199; and 5,429,299 also describe adhesive precoated orthodontic appliances.
Other useful packaging materials are disclosed in U.S. Pat. No. 5,762,192 (Jacobs et al.); U.S. Pat. No. 5,538,129 (Chester et al.); U.S. Pat. No. 5,348,154 (Jacobs et al.); U.S. Pat. No. 5,328,363 (Chester et al.); and U.S. Pat. No. 5,221,202 (James). In particular, illustrative packaging materials suitable for use in the present invention are disclosed in U.S. Pat. No. 5,772,192 at columns 2 and 3. The packaging materials keep the adhesive and the orthodontic appliances precoated with the adhesive stable at room temperature (about 22xc2x0 to 26xc2x0 C.) for at least 6 months, preferably at least 12 months, and at refrigerated temperature (about 35xc2x0 to 45xc2x0 C.) for at least 12 months, preferably at least 18 months.
Dispensing a desired amount of adhesive directly onto the base of the orthodontic appliance is another useful method. The adhesive can be dispensed using fine tipped dental instruments, such as direct extrusion through a syringe, brushes, or a disposable unit-dose delivery system. Once adhesive is placed on the orthodontic appliance, the appliance can be applied to the desired teeth surface. Excess adhesive (commonly referred to as xe2x80x9cflashxe2x80x9d) is then removed. The adhesive can then be exposed to actinic radiation to initiate the change in color from its initial color to a final color. Hardening or curing of the composition may occur simultaneously with the color change. In a preferred adhesive that comprises a photoinitiator system, the color change and curing can be accomplished using for example, a dental curing light. If alternative adhesives are thermally or redox cured, the color change may not occur until exposed to actinic radiation.
The inventive adhesive can also be used in indirect bonding methods, as disclosed in U.S. Pat. No. 5,971,754 (Sondhi et al.). In very brief summary, the method involves the following acts. First, an impression of the patient""s dental arch is taken. A model is made from the impression using plaster of Paris or xe2x80x9cstonexe2x80x9d model. A thin layer of separating medium is applied to the stone model and allowed to dry. A pencil mark is made across the labial surface of each replica tooth to assist in subsequent placement of orthodontic appliances. Using the inventive adhesive, the appliance is bonded to the replica tooth. The stark color contrast between the adhesive and the replica tooth providing for easy removal of excess flash and would be consistent with the orthodontist""s goal of minimizing working time. Subsequent processing steps in the indirect bonding method can be found in the U.S. Pat. No. 5,971,754 patent, and includes, e.g., making a transfer tray by placing a matrix material (e.g, Bioplast brand clear plastic sheet from Scheu Dental) over the model and appliances and using heat to soften the matrix material.
Conditioning a tooth surface may enhance adhesion of the orthodontic appliance to the tooth or teeth surface(s). Preferable the surfaces can be etched or primed prior to applying the adhesive. Preferably, an etching composition and/or priming composition are used at the locations on the tooth surface that a practitioner desires to place the materials of the present invention. Alternatively or in addition to using an etching composition, an air abrasion system may be used.
The adhesive can be photo-bleached using a variety of methods. It is convenient to use light sources that emit ultraviolet or visible light such as quartz halogen lamps, tungsten-halogen lamps, mercury lamps, plasma arcs, light emitting diodes and lasers.
Color Test
Initial and final colors were determined using a StellarNet Portable Spectrometer Model EPP2000C equipped with a 400 xcexcm fiber reflectance probe and SpectraWiz CIELAB colorimeter software (StellarNet, Inc., Oldsmar, Fla.).
To prepare samples, a small amount of adhesive is extruded onto a polyester liner at the bottom of a 1-inch diameter metal ring. A second liner is placed on top of the adhesive and the adhesive pressed between two plexiglass plates. The metal ring controls the thickness to 0.040 inches. In the case of uncured adhesive, the top plexiglass plate is removed. The sample is placed on top of a white reflectance standard (i.e., a white background). The fiberoptic probe is positioned 0.25 inches above the sample at a 45xc2x0 angle. Sample time was 1500 milliseconds. Color measurements are taken through the top polyester liner.
The cured samples were -prepared in the same manner except that the adhesive was cured while held between the two plexiglass plates for 3 minutes in a TRIAD 2000 light curing oven (Dentsply International, Inc., York, Pa.). The cured adhesive disk was removed from the mold and placed directly onto the white reflectance standard. The 0.25 inch distance and 45xc2x0 angle were maintained.
The L*a*b* system is based on a 3-dimensional color space with the positive X-axis representing red, the negative X-axis representing green, the positive Y-axis representing yellow, the negative Y-axis representing blue, and the Z-axis going from zero (black) to 100 (white) with the origin at 50. xcex94E* is a calculation of total color change in the three color dimensions and is described by the following equation:
xcex94E*=Square root((L1*xe2x88x92L2*)2+(a1*xe2x88x92a2*)2+(b1*xe2x88x92b2*)2)
where subscripts xe2x80x9c1xe2x80x9d indicates initial state and xe2x80x9c2xe2x80x9d indicates final state.

Adhesive for use in the oral environment having color-changing capabilities


The present invention relates to methods for treating neurological-urological conditions. This is accomplished by administration of at least one neurotoxin.

The present invention provides methods for treating neuronally-mediated urologic and related disorders, for example, benign prostatic hyperplasia (BPH) and prostatitis. This is accomplished by administering a composition that includes at least one neurotoxic compound or by conventional therapies.
Many medical conditions in urology are rooted in a spastic dysfunction of the sacral reflex arcs. Examples of such conditions include pelvic pain (e.g., interstitial cystitis, endometriosis, prostatodynia, urethral instability syndromes), pelvic myofascial elements (e.g., levator sphincter, dysmenorrhea, anal fistula, hemorrhoid), urinary incontinence (e.g., unstable bladder, unstable sphincter), prostate disorders (e.g., BPH, prostatitis, prostate cancer), recurrent infection (secondary to sphincter spasticity), and urinary retention (secondary to spastic sphincter, hypertrophied bladder neck) and neurogenic bladder dysfunction (e.g., Parkinsons""s Disease, spinal cord injury, stroke, multiple sclerosis, spasm reflex).
The prostate is a partially glandular and partially fibromuscular gland of the male reproductive system. During aging, the prostate tends to enlarge (hypertrophy). This prostatic enlargement can lead to urethral obstruction and voiding dysfunction.
Prostatic enlargement is a common occurrence in older men. Lytton et al. (Lytton, B., Emery, J. M. and Harvard, B. M. [1973] 99: 639-645) estimated that a 45 year old male had a 10% risk of prostate surgery by age 70. The U.S. Census Report estimates that there are 30 million people today over age 65. This segment of the population is projected to rise to 50 million over the next 30 years. Therefore, the number of men with prostatic enlargement also will increase. According to draft reports of the National Kidney and Urologic Disease Advisory Board, 425,000 prostatectomies were performed in the United States in 1989. Based on population growth estimates, the number of prostatectomies performed annually will rise to 800,000/year by the year 2020.
The urethra passes through the prostate (prostatic urethra) as it courses to the external urethral orifice. The prostate has five distinct lobes that are apparent at 12 weeks in the human fetus (Lowsley, O. S. Am. J. Anat. [1912] 13: 299-349.). Although the lobular branching found in the fetus is not visible in the prepubescent prostate, the lateral middle anterior and posterior lobes are used to describe the enlarged prostate.
A more recent viewpoint is that the prostate also is comprised of several morphologically distinct zones (McNeal, J. Urol. Clin. North Am. [1990] 17(3): 477-486). The majority of the glandular volume is composed of the peripheral zone (xcx9c70-75%). The remainder of glandular volume is divided into the central zone (xcx9c20-25%), the transition zone (xcx9c5-10%) and the periurethral glandular zone (xcx9c1%).
McNeal (1990) reported that BPH develops in the transition zone and the periurethral glandular zone. BPH nodules develop either within or immediately adjacent to the pre-prostatic sphincteric zone. The transition zone is a small region close to the urethra intimately related to the proximal urethral sphincter. The stroma of the transition zone is dense and compact, and is unusually susceptible to neurologically-induced disturbances of growth control. Its glands penetrate the sphincter, while sphincter muscle fibers penetrate the transition stroma. The periurethral glandular zone has a similar urogenic sinus origin as the transition zone.
BPH may be associated with increased amounts of stroma relative to epithelium (Bartsch, G., Muller, H. R., Oberholzer, M., Rohr, H., P., J. Urol. [1979] 122: 487-491). A significant portion of the stroma is smooth muscle (McNeal, 1990) which is under sympathetic nervous control. The contractile properties of this smooth muscle could account for the dynamic component of obstruction in BPH (Bruschini, H. et al. [1978] Invest. Urol. 15(4): 288-90; Lepor, H. [1990] Urol. Clin. North Am. 17(3): 651-658).
In addition to sympathetic control of prostatic stroma, the prostate is highly innervated. The prostate nerve fibers enter the prostate from the posterior lateral aspect, with a concentration of ganglia near the junction between the prostate and the seminal vesicles (Maggi, C. A., ed. [1993] Nervous control of the Urogenital System, Harwood Academic Publishers; Higgins, J. R. A. and Gosling, J. A. [1989] Prostate Suppl. 2: 5-16). Acetylcholine (ACH), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and noradrenaline fibers have been described in this gland. A rich plexus of ACH-positive nerve cell bodies is associated with secretory acini in all parts of the gland. Some of the ACH fibers also contain NPY neurons. VIP-containing neurons have been found associated with ACH-containing nerve cell bodies. Occasional neurons have been found between the ACH-staining nerve fibers, suggesting that both NPY and noradrenergic neurons supply smooth muscle (Higgins, J. R. A. and Gosling, J. A. [1989] Prostate Suppl. 2: 5-16).
Autonomic nerves are distributed evenly between the central and peripheral zones of the prostate (Higgins, J. R. A. and Gosling, J. A. [1989] Prostate Suppl. 2: 5-16). Peripheral neuronal control is similar. In addition, there is no difference in the type of nerve fibers found associated with either epithelial or stromal elements of the gland.
The anatomical studies of nerve fiber types in the prostate, coupled with other studies of innervation of prostatic stroma (Brushing H., Schmidt, R. A., Tanagho, E. A., [1978] Invest. Urol. 15(4): 288-290; Watanabe, H., Shima, M., Kojima, M., Ohe, H. L. [1989] Pharmacol. Res. 21(Suppl 2): 85-94) suggest that cholinergic innervation influences epithelial behavior, while adrenergic innervation influences stromal tonus (excitability). These observations have provided a rationale for the use of, for example, alpha blockers in the treatment of BPH. The effects of alpha blockers (Downie, J. W. and Bialik, G. J. [1988] J. Pharmacol. Exp. Ther. 246(1): 352-358) can also account for improvements in symptoms of BPH as a result of dampening of dysfunctional striated sphincter behavior by the alpha blockers.
Studies have also shown that there are several tachykinins (for example, substance P [SP], calcitonin gene related peptide [CGRP], neurokinin A, bradykinin, and nerve growth factor [NGF]) that can influence the tonus of smooth muscle (Hakanson, et al., [1987] Neuroscience 21(3): 943-950). Neurotransmitter receptors have been quantified throughout the prostate (e.g., NPY, VIP, SP, leu-enkephalin (L-enk), met-enkephalin, 5-HT, somatostatin, acetylcholinesterase positive fibers (ACTH), and dopamine beta-hydroxylase (DBH) (Crowe, R., Chapple, C. R., Burnstock, G. The Human Prostate Gland: A Histochemical and Immunohistochemical Study of Neuropeptides, Serotonins, Dopamine beta-Hydroxylase and Acetylcholinesterase in Autonomic Nerves and Ganglia). There is some variation in receptor density at different prostatic sites in benign prostatic hyperplasia.
Changes in electrophysiologically recorded cellular behavior and in concentration of neuropeptides within the spinal cord have been shown to be a secondary consequence of mechanical pinch to the tail muscles of a rat, catheter stimulation of the posterior urethra, and electrostimulation of a peripheral nerve. Dyssynergia between the detrusor and the urethral sphincter is a significant finding in prostatodynia patients. Denervation of the prostate has been shown to produce dramatic changes within the prostatic epithelium. Thus there is evidence that experimentally induced alterations in neurological influences can be produced in the sacral, spinal cord, bladder or urethra through mechano-, electro-, chemical or thermal (microwave, laser) methods to change irritative behavior. However, there have been no known attempts to use neurotoxins for therapeutic applications.
There is poor correlation between the degree of prostatic enlargement and the severity of symptoms. While 80% of men age 70 show BPH on transrectal ultrasound scans, only 20% seek surgery (Coffey, D. S. and Walsh, P. C. [1990] Urol. Clin. North Am. 17(3): 461-475), the treatment of choice for BPH (Fowler, F. J. Jr., Wennberg, J. E., Timothy, R. P. [1988] J. Amer. Med. Assoc., 259(20): 3022-3028). Symptoms of irritation may far exceed symptoms expected based on the size of the prostate. Symptoms may improve after surgical treatment of BPH by procedures such as transurethral resection of the prostate (TURP) (Christensen, Aagaard, M. M. J., Madsen, P. O. [1990] Urol. Clin. North Am. 17(3): 621-629), balloon dilation (Dowd, J. B. and Smith, J. J. III [1990] Urol. Clin. North Am. 17(3): 671-677), or prostatic hyperthermia (Baert, L., Ameye, F., Willemen, P., et al., [1990] J. Urol. 144: 1383-1386). However, symptoms persist in as many as 15% of all BPH patients (Baert, L., Ameye, F., Willemen, P., et al., [1990] J. Urol. 144: 1383-1386; Wennberg, J. E., Mullly, A. G., Hanley, D., Timothy, R. P., Fowler, F. J., Roos, R. P., Barry, M. J. et al., [1988] J. Amer. Med. Assoc. 259: 3027-3030). Up to 25% of BPH patients have secondary procedures in long term follow-up studies, suggesting that surgical approaches do not address the fundamental mechanisms that produce BPH, i.e., the faulty neurological influence (control mechanism) on the integrity of the lower urinary tract.
The need for repeated surgeries, the morbidity and mortality associated with TURP and the cost of surgery have led to the development of some non-surgical approaches such as androgen ablation (McConnell, J. D., [1990] Urol. Clin. North Am. 17(3): 661-670) and the use of alpha blockers discussed above, but few medical or surgical treatments to date have produced a restoration of void behavior to normal state (flow rate of about 25 cc/sec and void volume of about 400 cc).
The present invention uses chemical and non-chemical methods, particularly neurotoxins, to modulate neuronally-mediated urologic and related disorders. For example, such methods can be used to treat BPH and related conditions such as prostatitis. The instant invention also may remove triggers of changes in the CNS by non-chemical methods including biofeedback, or by chemical methods that treat BPH and other urological conditions by the administration of substances that block various neurological activities, such as, for example, selected neurotoxins.
It is an object of the instant invention to provide safe, inexpensive, out patient methods for the prevention and treatment of urological-neurological dysfunctional states or conditions, for example, prostatic enlargement.
It is a further object of the present invention to provide compositions for this therapeutic goal. It is a still further object of the present invention to provide dosages and methods of administration for compositions useful for the prevention and treatment of neurological-urological conditions.
Other objects of the present invention will be readily apparent to those of ordinary skill in the art.
In accordance with one aspect of the present invention, there are provided methods of treating urological-neurological conditions in mammals, said methods comprising the step of administering a therapeutically effective amount of at least one neurotoxin to such a mammal. It is preferred that the neurotoxin inhibits synaptic function. Such inhibition produces selective denervation, and, for example, atrophy of the prostate and reversal of irritative symptoms associated with prostatic enlargement. In one embodiment of the instant invention, the neurotoxin induces dysfunction of the presynaptic neuronal terminal by specific binding and blockade of acetylcholine release at myoneural junctions. Such a neurotoxin can be, for example, botulinum toxin type A (e.g., BOTOX, Allergan).
Preferably, the neurotoxin is safe, highly selective and easy to deliver, including when combined with other therapies. Other useful neurotoxins include capsaicin, resinoferatoxin and xcex1-bungotoxin. Delivery of the neurotoxin can be by any suitable means. A convenient and localized method of delivery is by injection.
A therapeutically effective amount of the neurotoxin is the dosage sufficient to inhibit neuronal activity for at least one week, more preferably one month, most preferably for approximately 6 to 8 months or longer. Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. Neurotoxin can be delivered serially (i.e., one time per month, one time per every six months) so that the therapeutic effect can be optimized. Such a dosage schedule is readily determined by one skilled in the art based on, e.g., patient size and the condition to be treated, and will depend on many factors, including the neurotoxin selected, the condition to be treated, the degree of irritation, and other variables. One suggested course of treatment for BPH is 200 units every three days up to the LD50 for Botox or about 2500 units.
The aforementioned methods of treatment should be particularly useful for the long-term control of neurological-urological disorders, e.g., the symptoms of prostatic enlargement, without the need for surgical intervention. Furthermore, the methods of the instant invention provide for control of neurological-urological disorders, e.g., BPH and related conditions, in a highly selective manner, without the potential side effects and treatment failures associated with current treatment modalities.
xe2x80x9cUrological-neurological condition or disorderxe2x80x9d includes many medical conditions in urology rooted in a spastic dysfunction and/or degeneration of the sacral reflex arcs. Examples of such conditions include pelvic pain (e.g., interstitial cystitis, endometriosis, prostatodynia, urethral instability syndromes), pelvic myofascial elements (e.g., levator sphincter, dysmenorrhea, anal fistula, hemorrhoid), urinary incontinence (e.g., motor or sensory, unstable bladder, unstable sphincter), prostate disorders (e.g., BPH, prostate cancer), recurrent infection (secondary to sphincter spasticity), and urinary retention (secondary to spastic sphincter, hypertrophied bladder neck), and neurogenic bladder dysfunction (e.g., Parkinson""s Disease, spinal cord injury, stroke, multiple sclerosis, spasm reflex) and other such urological conditions of a nervous etiology.
The prostatic enlargement that can be treated according to the methods of the instant invention can be of any etiology. The instant invention is particularly suited for the treatment of prostatic hyperplasia, especially benign prostatic hyperplasia. The present invention can also be used for the treatment of enlargement of the prostate with inflammation (prostatitis), particularly abacterial prostatitis. In addition, the methods of the instant invention can be used for the treatment of prostatodynia.
Without being bound by theory, the basis for the treatment of the neurological-urological conditions according to the instant invention is the removal or modulation of the neural basis for the dysfunctional regulation of the affected tissue. For example, the modulation of the neural basis of prostate glandular dysfunction can be accomplished by any non-surgical means known in the art. Such means can include, for example, biofeedback, xcex1-blockers, pharmacological methods, and the use of one or more neurotoxins to inhibit synaptic function in the affected gland. It is preferred that the neurotoxin cause long-lasting inhibition of synaptic function, preferably greater than one week, more preferably greater than one month, most preferably six to eight months or longer. Such neurotoxins can include, for example, capsaicin, resinoferatoxin, xcex1-bungotoxin, terodotoxin and botulinum toxin. Botulinum toxin is a preferred neurotoxin according to the instant invention, particularly botulinum toxin A, more particularly BOTOX (Allergan).
The toxin can be formulated in any pharmaceutically acceptable formulation in any pharmaceutically acceptable form. Such forms and formulations include liquids, powders, creams, emulsions, pills, troches, suppositories, suspensions, solutions, and the like. The toxin can also be used in any pharmaceutically acceptable form supplied by any manufacturer.
In a preferred embodiment in accordance with the method of the instant invention, the neurotoxin is botulinum toxin type A. Therapeutically effective amounts of botulinum toxin can be any amounts or doses that are less than a toxic dose, for example, less than about 3000 IU/70 kg male, preferably between 100 IU/70 kg male to 1200 IU/70 kg. The dosages can be given as a single dose, or as divided doses, for example, divided over the course of four weeks.
The neurotoxins of the instant invention can be administered by any suitable means. In the preferred embodiment of the invention, botulinum toxin is administered by injection Such injection can be administered to any affected area. For example, the neurotoxin can be injected urethroscopically into the prostate with 200 IU with single or serial dosing. Preferably, the neurotoxin is injected every three days until a therapeutic effect is achieved or up to about 2500 units.
The following techniques are used in this invention:
Tissue Preparation for Light Microscopy
Tissues are fixed in 6% paraformaldehyde in 0.1 M phosphate buffer, pH 7.2, for 24 hours, dehydrated in graded alcohol and xylene, and embedded in paraffin. Sections are cut and stained with appropriate stains, such as hematoxylin/eosin.
Tissue Preparation for Electron Microscopy
Tissues are collected and fixed in 2.5% glutaraldehyde in 0.1 M phosphate buffer, pH 7.2, for 1 hour at 4xc2x0 C., then incubated with 0.1% osmium tetroxide for 1 hour and embedded in EPON. Ultrathin sections (80 nm) are prepared and stained with lead citrate/uranyl acetate and examined with an electron microscope (Philips, model 201).
Tunel Stain for Apoptosis
The tissue is fixed and embedded as described above. The tissues are deparaffinized and reacted with Proteinase K (Boehringer). They are further treated with peroxidase and TDT enzyme and placed in a humidifier set at 37xc2x0 C. for one hour. The sections are washed and anti-digoxigenin-peroxidase is added for 30 minutes, followed by staining with nickel-DAB (diaminobenzene).
Immunohistochemistry Studies
The presence of the neuropeptides VIP, SP, NPY, L-Enk and calcitonin gene-related peptide (CGRP) as well as the expression of transforming growth factor beta (TGF-beta), transforming growth factor alpha (TGF-alpha), epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) are determined in prostatic tissues using appropriate monoclonal antibodies. Use of neurotoxins results in prostatic atrophy, which should be reflected by lower levels of growth factors in treated prostatic tissue.
Sections are incubated overnight at room temperature with primary antibodies followed by immunostaining with avidin-biotin-peroxidase (Vectastain Elite ABC, Vector Labs, USA). Rabbit polyclonal antiserum against the neurotransmitters VIP, CGRP, SP, NPY and L-Enk (Peninsula Labs, USA) is used in these preparations, at dilutions of 1:8000 to 1:12,000. Immunocytochemical controls consist of preabsorbing the primary antiserum with appropriate antigen, or their substitution with normal serum (Blasi, J., Chapman, E. R., Yamaskai, S., Binz, T., Niemann, H and Jahn, R. [1993] The EMBO Journal 12: 4821-4828; Black, J. D. and Dolly, J. O. [1986] J. Cell Biol. 103; 535-544; Linial, M. [1995] Is. J. Med. Sci. 31: 591-595). After mounting on slides, sections are counterstained with eosin, dehydrated and coverslipped.
Western Blot Analysis of Growth Factor Expression
Treated and untreated prostate cell homogenates are examined for expression of growth factors by Western blot analysis. Cell homogenate protein is separated by electrophoresis on SDS-PAGE (7%), then transferred electrophoretically overnight to nitrocellulose paper (Towbin, H., et al., [1979] Proc. Nat. Acad. Sci. 76(9): 4350-4379). The nitrocellulose paper is soaked for one hour at room temperature in 0.5% non-fat dry milk dissolved in phosphate buffered saline, and further soaked overnight at 4xc2x0 C. in blocking solution (2% bovine serum albumin in 10 mM Tris/0.15 M NaCl/0.1% sodium azide, pH 7.4). The nitrocellulose membranes are incubated with antibodies (IgG fractions of anti-TGF-beta, anti-TGF-alpha, anti-EGF and anti-bFGF) purified by protein A (1xc3x97106 cpm/ml) in blocking buffer for 1 hour. The membrane is washed with PBS containing Nonidet P-40 between incubations. X-O-mat AR2 film (Kodak) is exposed to the membrane at xe2x88x9270xc2x0 C. and films are developed to examine the expression of growth factors.
Determination of c-fos and c-myc Expression
Expression of c-fos and c-myc in treated and untreated prostatic tissue is determined by Northern blot analysis as follows. Tissue is homogenized in lysis buffer for 15 seconds or until the tissue homogenizes. Sodium acetate is added and the solution in mixed by swirling. An equal volume of water-saturated phenol is added and mixed by inversion, followed by addition of chloroform/isoamyl alcohol. The solution is vortexed vigorously for 30 seconds, and allowed to settle on ice for 15 minutes. The solution is centrifuged for 10-20 minutes at 4xc2x0 C. After centrifugation, the aqueous phase is carefully aspirated and placed in a new polypropylene tube. One volume of isopropanol is added and the solution is mixed by swirling. The solution is placed in a xe2x88x9220xc2x0 C. freezer for at least 60 minutes to precipitate RNA. After precipitation, the tube is centrifuged for 10 minutes, and the supernatant is decanted, leaving the RNA pellet. One ml of ethanol is added, and the tube is centrifuged for an additional 10 minutes. The aqueous phase is discarded, and the pellet is washed with 100% ethanol by vortexing. The RNA pellet is redissolved in 0.4 ml of lysis buffer. The RNA is reprecipitated by the addition of 100% ethanol and incubation at xe2x88x9220xc2x0 C. freezer for at least 60 minutes. The solution is centrifuged and the supernatant discarded. RNA concentration is determined by diluting 5 xcexcL of sample into 995 xcexcL of DEPC water and measuring the ratio of absorbance at 260/280 nm.

Use of neurotoxin therapy for treatment of urologic and related disorders


A fluid handling device to assist in the mixing or separation of two or more fluids utilizing a stack of two types of alternating plates. A first plate has an aperture; a second plate has peripheral spaces around which the fluids may flow. Both types of plates are provided with a plurality of projections that serve to space the plates apart and to provide additional turbulence to the fluids as they flow around the projections. The fluids are forced to proceed back and forth through the alternating plates. The plates may be designed to fit within a housing of circular or polygonal cross-section. The projections may be tapered or non-tapered. The projections may be circular or polygonal in cross-section. Further the heights of the projections may vary to adjust the separation between adjacent pairs of plates to obtain the appropriate degree of turbulence for optimum mixing or separation of the fluids. Fluids may be introduced into the housing containing the stack of plates at various points as required by the particular fluids being handled.

Not Applicable.
Not Applicable.
1. Field of the Invention
The present invention relates to fluid handling devices, and in particular, to fluid handling devices employing a plurality of stacked plates for dispersal, separation and turbulent mixing of fluids.
2. Brief Description of the Related Art
There are numerous applications requiring the continuous mixing of two or more fluids. Example includes foams, paints, solvents, and components of chemical processes. Such fluids may have varying degrees of viscosity and miscibility which can render thorough mixing difficult to achieve on a continuous basis. Information relevant to attempts to address this problem can be found in the following U.S. patents. These references mentioned in this background section are not admitted to be prior art with respect to the present invention.
A typical example of an in-line mixing device is disclosed in U.S. Pat. No. 3,941,355 to Simpson. Simpson discloses a device for mixing foam ingredients. A series of longitudinally spaced discs are disposed on a shaft within a cylindrical bore. The discs have radial slots on alternating sides of the discs so that the fluids are forced to take a path which flows through the alternating slots and divides and flows around the shaft in the space between the discs. U.S. Pat. No. 3,363,412 to Cole discloses a similar pattern of alternating cutouts on the sides of a plurality of stacked discs. However, Cole does not have the central shaft of Simpson.
U.S. Pat. No. 5,547,281 to Brooks discloses a mixing apparatus having first and second end walls and an intermediate wall disposed between the end walls in a tubular member. The end walls have at least one aperture and the intermediate wall is spaced from the interior of the tubular member to form an annular passage. The fluids to be mixed therefore flow through the apertures in the first end wall, through the annular passage around the intermediate wall, and then exit through the aperture in the second end wall.
U.S. Pat. No. 5,232,283 to Goebel et al. discloses a mixing apparatus comprising a tray with an aperture in the middle. A cap with opposed openings covers the aperture. Fluids pass through the opening into a pan below the tray. A tube encircling the aperture below the cap has notches to allow the fluids to enter the pan. Radially spaced risers extending from the bottom of the pan have upper ends above the notches and below the tray. The risers have openings through which the fluids pass.
U.S. Pat. No. 4,441,823 to Power discloses a liquid mixer with a plurality of slotted plates spaced apart within a chamber. The slots are angled to the exit face of the plate so as to induce turbulence. The slots are preferably radially disposed in the circular plates.
U.S. Pat. No. 5,863,129 to Smith discloses a mixing device comprising stacks of three different types of cylindrical mixing elements. Each of the mixing elements has a pair of inlets, a central chamber and an outlet.
U.S. Pat. No. 5,997,283 to Spiros discloses an electrolysis system in which a stack of plates have a polygonal shape and have projections by which the plates are spaced apart.
Each of these references suffers from the disadvantage of not inducing sufficient turbulence and intermingling of the fluids to thoroughly mix fluids of varying viscosity and miscibility. Further, fluid separation may also be accomplished more efficiently by devices having enhanced resistance to fluid motion, which may be developed by structures related to the same type of structures that enhance turbulence.
The limitations of the prior art are overcome by the present invention as described below.
The present invention is directed to a device that satisfies the needs identified above. The invention is a fluid handling device to assist in the mixing or separation of two or more fluids. Depending on the application, structures in the device enhance turbulence in moving fluids or provide resistance to fluid motion. In the first case mixing is enhanced; in the second, separation is enhanced.
The device utilizes a stack of plates. Two types of plates are alternated to achieve the mixing or separation effect. One type of plate has peripheral spaces around which the fluids may flow; the other type of plate has at least one aperture, which may be centrally located. Both types of plates are provided with a plurality of projections that serve to space the plates apart and to provide additional turbulent mixing or enhanced fluid resistance of the fluids as they flow around the projections. When being mixed, the fluids are forced to proceed back and forth through the alternating plates until thoroughly mixed.
The device may also be employed for separation of fluid components based on varying density of the fluid components. The preferred embodiment for fluid separation mounts the plates for rotation within a housing so that the separation effect occurs by centrifugal effects enhanced by the resistance to fluid motion provided by the plates and projections within the device.
In a preferred embodiment of the present invention directed to mixing of two or more fluids, the fluids may be introduced through a plate with at least one aperture, then forced around the periphery of the next plate and so forth. When mixing two or more fluids, the fluid flow is alternately divided and recombined for thorough mixing.
While the plates may be adapted for use in a cylindrical housing, the invention is not so limited. The plates may, for example, be designed to fit within a housing of polygonal cross-section. In such a case, the second type of plate having the central aperture may have the same polygonal cross-section. The first type of plate is then shaped so that the extreme points on the periphery fit against the walls of the housing while the peripheral segments between these extreme points are withdrawn from the walls of the housing so as to provide gaps around which the fluids may flow.
The projections may be tapered and circular in cross-section. Other shapes, both tapered and non-tapered, are contemplated as being within the scope of the invention. The projections, may for example, be square, or more generally, polygonal in cross-section. More angular shapes may assist in turbulent mixing or provide enhanced fluid resistance. These more angular shapes may be desirable depending on the viscosity of the fluids. Various numbers and arrangements of the projections are contemplated as being within the scope of the invention. Further the heights of the projections may vary depending upon the application. For example, depending on the viscosity of the fluids being handled, it is desirable to adjust the separation between adjacent pairs of plates to obtain the appropriate degree of turbulence for optimum mixing or fluid separation. The mixing effect may be enhanced by placing a plurality of spheres between the projections. The spheres are sized to have a diameter less than the height between the plates and less than the distance separating the projections so that the spheres are able to tumble in the fluids. The tumbling action not only enhances mixing but also may be useful in grinding and dispersing solid particles in the fluids.
The device is intended to be applicable to the mixing or separation of a plurality of fluids. The fluids may be introduced into the housing containing the stack of plates at various points as required by the particular fluids being mixed. For example, two fluids to be mixed may advantageously be introduced at one end of the housing and the two fluids will be mixed together through the entire series of plates. Alternatively, one or more fluids may be introduced into, or removed from, the housing at points along the fluid path after one or more fluids have been introduced into the first end of the housing.
The device may be mounted both horizontally or vertically with respect to the major axis of the device. The plates may be interlocked and mounted for rotation within the housing for separation or mixing of fluids. The device may be employed for both mixing and separation operations simultaneously. For example, two liquids, at least one of which contains a gaseous component, could be introduced at one end of the device. As the two liquids are mixed, the gaseous component, from the effect of gravity alone or as enhanced by centrifugal effects, would tend to separate from the mixed liquids and could therefore be drawn off at some intermediate point from the device.
The description above has used the term xe2x80x9cfluidxe2x80x9d to mean both liquids and gases, including liquids and gases carrying entrained and suspended solids. The plates may be constructed of any suitable material for the type of fluids being mixed.
It is therefore an object of the present invention to provide for device to assist in the mixing or separation or two or more fluids in which a stack of two types of plates are alternated to achieve a fluid resistance effect.
It is a further object of the present invention to provide for such a fluid handling device is which one type of plate has peripheral spaces around which the fluids may flow and the other type of plate has at least one aperture which may be centrally located.
It is also an object of the present invention to provide such a fluid handling device in which the plates are spaced apart by pluralities of projections which assist in the turbulent mixing or separation of the fluids.
It is a still further object of the present invention to provide such a fluid handling device in which the stacked plates are interlocked together and mounted for rotation within a housing.
These and other features, objects and advantages of the present invention will become better understood from a consideration of the following detailed description of the preferred embodiments and appended claims in conjunction with the drawings as described following:


The invention includes a method and a device for determining an emotive index for a message. In the method, a message is received and words in the message are identified for analysis. An emotive index corresponding to the identified words is then determined. The emotive index is preferably a function of a word count index corresponding to the number of identified words, an affinity index and an antagonism index. A device according to the present invention includes a computer readable storage medium having encoded thereon computer readable instructions capable of instructing a computer to carry out the method.

1. Field of the Invention
The present invention relates generally to devices and methods of determining the emotion expressed in a message.
2. Discussion of Related Art
In the prior art, there are devices and methods of determining a vector representing the content of a message. In one such method and device, a natural language processing system uses unformatted naturally occurring text and generates a subject vector representation of the text, which may be an entire document or a part thereof such as its title, a paragraph, clause, or a sentence therein. The subject codes which are used are obtained from a lexical database and the subject code(s) for each word in the text is looked up and assigned from the database. The database may be a dictionary or other word resource which has a semantic classification scheme as designators of subject domains. Various meanings or senses of a word may have assigned thereto multiple, different subject codes and psycholinguistically justified sense meaning disambiguation is used to select the most appropriate subject field code. Preferably, an ordered set of sentence level heuristics is used which is based on the statistical probability or likelihood of one of the plurality of codes being the most appropriate one of the plurality. The subject codes produce a weighted, fixed-length vector (regardless of the length of the document) which represents the semantic content thereof and may be used for various purposes such as information retrieval, categorization of texts, machine translation, document detection, question answering, and generally for extracting knowledge from the document. The system has particular utility in classifying documents by their general subject matter and retrieving documents relevant to a query. Such devices and methods do not provide an indication of the emotion expressed in the message.

Device and method of determining emotive index corresponding to a message

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